Use of cigarettes and smokeless tobacco (SLT) in the U.S. costs over 400,000 lives and $100 billion annually. These tobacco-related deaths and health care costs are due to tobacco-delivered toxicants, especially carcinogens. Tobacco cessation is the most effective way of reducing toxicant exposure, though relapse rates are high. High relapse rates and continued tobacco use have provoked interest in harm reduction for people who continue to use tobacco. Harm reduction for tobacco users can involve lowering the total adverse health consequences of continued tobacco use by reducing toxicant exposure. The tobacco industry appears to embrace this type of harm reduction, and markets several potential reduced exposure products (PREPs) for smokers and SLT users. The National Cancer Institute and Institute of Medicine argue for objective testing of these PREPs. No accepted testing method exists, though we have had success using a short-term clinical model for evaluating cigarette-like PREPs for smokers. This short-term model could be improved and must be adapted to evaluate oral PREPs for SLT users and smokers. A longer-term model is necessary to measure PREP-induced reductions in carcinogen exposure. The specific aims of this proposal are to: (1) Improve the short-term clinical model for evaluating cigarette-like PREPs by allowing ad libitum puffing so that PREP-induced changes in smoking behavior can be measured, and introducing pre- and post-exposure blood sampling so that PREP nicotine delivery can be assessed. (2) Adapt the short-term clinical model so that it can be used to evaluate oral products intended for SLT users and/or smokers, and (3) Develop a longer-term clinical model for evaluating PREP carcinogen delivery. This project's overarching goal is to establish a clinical model that can be used to evaluate the marketing claims and harm reduction potential of PREPs for tobacco users. The project is consistent with NCI's Plans and Priorities for Cancer Research in 2004: "Smokers may feel a false sense of security that they can significantly reduce their risk of disease by using these new products [PREPs], when no data exists to suggest that they are in fact less harmful. Scientists must examine the toxicity of these products as well as evaluate whether or not 'harm reduction' is a viable public health strategy." This proposal's clinical model will likely be an important component of a comprehensive approach to predict if PREPs for tobacco users increase, decrease, or fail to change tobacco's health risks.